Female Urology Nocturia: Current Levels of Evidence and Recommendations From the International Consultation on Male Lower Urinary Tract Symptoms Stephen D. Marshall, Dima Raskolnikov, Marco H. Blanker, Hashim Hashim, Varant Kupelian, Kari A. O. Tikkinen, Koji Yoshimura, Marcus J. Drake, and Jeffrey P. Weiss OBJECTIVE METHODS


To evaluate published evidence on nocturia in men and derive expert recommendations. The International Consultations on Urological DiseaseseSociete Internationale d’Urologie convened a Consultation of experts on male lower urinary tract symptoms. The Consultation assigned standardized levels of evidence and grades of recommendation to various studies of nocturia epidemiology, pathophysiology, assessment, and treatment. Evidence review and consensus recommendations were made in the areas of epidemiology, pathophysiology, assessment, and treatment. The review presents a condensed summary of the International Consultations on Urological DiseaseseSociete Internationale d’Urologie evaluation of nocturia, which offers contemporaneous expert consensus on this topic, with an assessment algorithm emphasizing the potential contribution of systemic conditions to the symptom. UROLOGY -: -e-, 2015.  2015 Elsevier Inc.


octuria, one of the storage-type lower urinary tract symptoms (LUTS), is defined by the International Continence Society as the complaint of waking at night to void.1 Despite this simple definition, nocturia is idiosyncratic in a number of ways. For example, nocturia of equivalent frequency causes markedly different reductions in quality of life (QoL) for different people. Consequently, QoL improvements deriving from treatment responses may differ between study populations. In some patients, nocturia progresses slowly, whereas in others, it remains stable or regresses with time. Finally, nocturia is multifactorial in etiology, making both assessment and treatment a potential challenge. This Financial Disclosure: Hashim Hashim is a consultant for Allergan, American Medical Systems, and Astellas; Marcus J. Drake is a consultant for Allergan, Astellas, and Ferring; and Jeffrey P. Weiss is a consultant for Ferring, Pfizer, Astellas, Allergan, Vantia, and Symptelligence. The remaining authors declare that they have no relevant financial interests. From the Department of Urology, SUNY Downstate Medical Center, Brooklyn, NY; the Department of General Practice, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; the University of Bristol and Bristol Urological Institute, Southmead Hospital, Bristol, United Kingdom; the New England Research Institutes, Watertown, MA; the Department of Urology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; the Departments of Urology and Public Health, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; and the Department of Urology, Shizuoka General Hospital, Shizuoka, Japan Address correspondence to: Marcus J. Drake, D.M., F.R.C.S.(Urol.), University of Bristol and Bristol Urological Institute, Southmead Hospital, Bristol BS10 5NB, United Kingdom. E-mail: [email protected] Submitted: November 14, 2014, accepted (with revisions): February 17, 2015

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challenge is an especially important one, however, as nocturia may indicate serious underlying illness. Illnesses such as cardiovascular, renal, or endocrine disease can disrupt water and salt homeostasis, resulting in increased production of urine.2 For this reason, even one nightly void may be considered a progression from no nocturia and thus an opportunity for secondary prevention. In such contexts, where the pathophysiology of nocturia is not in the lower urinary tract but reflecting systemic disease, alluding to it as LUTS are potentially misleading. The body of literature describing the evaluation and management of nocturia has expanded at a rapid rate. For this reason, in 2012, the International Consultations on Urological Diseases (ICUD) partnered with the Societe Internationale d’Urologie (SIU) to convene a Consultation on male LUTS. The goal of this Consultation was to use established criteria to assign objective levels of evidence (LOEs, 1 through 4) and grades of recommendation (GORs, A through D) to the most salient research in the field.3 The purpose of this review is to present a condensed summary of the ICUD-SIU evaluation of nocturia, incorporating additional subsequent panel review of the evidence base, which offers contemporaneous expert consensus on this topic. LOEs and GORs are presented here as the verbatim conclusions of the ICUD-SIU panel, with more detailed descriptions published elsewhere.4 Where published evidence was found to be sparse, but the committee considered a recommendation was required, the GOR is given without any LOE. http://dx.doi.org/10.1016/j.urology.2015.02.043 0090-4295/15


EPIDEMIOLOGY Prevalence Studies of nocturia prevalence have demonstrated that it is relatively common in both genders and all age groups. For example, in the population-based Finnish National Nocturia and Overactive Bladder Study, 1 of 8 men and women 18-79 years old reported at least 2 voids per night.5 Among young respondents, nocturia was more common in women than men, but this gender difference disappeared after middle age. Incidence The incidence of nocturia is not well understood, as the required longitudinal studies are difficult to perform. In the community-based Krimpen study, for example, nocturia was assessed longitudinally with frequency-volume charts over a period of several years.6 Overall incidence and remission rates for nocturia 2 voids per night after 2 years were 24% and 37%, respectively. Considerable fluctuation was noted at different study time points. Bother and Impact on Quality of Life Sleep disturbance is an important cause of the increased morbidity that is associated with nocturia. However, one nightly void does not appear to be sufficiently disruptive to cause significant bother in most patients. In the Finnish National Nocturia and Overactive Bladder Study, for example, the majority of people reported having bother when the number of nocturia episodes was 2, and 2 voids per night was associated with an impaired Health Related Quality of Life. Two nocturia episodes impaired Health Related Quality of Life compared with those with no nocturia.7 Impact of Nocturia: Falls, Fractures, Mortality, and Productivity Much of the increased mortality associated with nocturia may be due to the risk of hipfracture in patients who frequently wake to void. Interestingly, in a study of men aged 40-80 years, nocturia 2 voids per night was an ageindependent risk factor for hip fracture.8 Conclusions The ICUD committee considered that nocturia is a highly prevalent symptom, with similar overall prevalence in both genders. Prevalence increases more markedly with age in men. The literature on the incidence of nocturia remains relatively sparse. Incidence of nocturia increases with age, but significant short-term fluctuation in nocturia severity in individuals makes studies on incidence challenging. Two or more episodes of nocturia per night constitutes clinically meaningful nocturia severity in the general population, affecting QoL and perceived health, whereas a single episode usually does not. Nocturia has been suggested to increase risk of falls, fractures, death, and impaired productivity.4 2

Recommendations The ICUD committee considered that epidemiologic studies need to use strictly defined and clearly stated criteria of terminology and assessment. Approaches to identify intraindividual variation and other confounding influences need to be considered. Longitudinal studies using high-quality methodology remain a priority requirement. Nocturia of twice or more per night may be a threshold of clinical significance in the general population. However, this threshold is not irrefutably established and should not be extrapolated to subpopulations. Research into all grades of nocturia severity may yield information of clinical relevance.4

PATHOPHYSIOLOGY Classification and Risk Factors Nocturia may be divided into the following 5 causative categories: (1) Bladder storage problems, (2) Twenty-four-hour (global) polyuria (>40 mL/kg urine output over a 24-hour period), (3) Nocturnal polyuria1 (NP; nocturnal output exceeding 20% of 24-hour urine output in the young, or 33% of urine output in people aged >65 years), (4) Sleep disorders, (5) Mixed etiology. Examples of bladder storage problems include overactive bladder (OAB) and urinary tract infection. Global polyuria is commonly caused by polydipsia and by conditions such as diabetes insipidus. NP is seen with peripheral edema and circadian defects in arginine vasopressin secretion, among many other conditions.2 Sleep disorders may be primary or secondary. Nocturia of mixed etiology is caused by combinations of any of the aforementioned. A summary of the ICUD-SIU conclusions regarding common risk factors for nocturia is presented in Table 1. Conclusions and Recommendations The ICUD committee considered that the pathophysiology of nocturia can be divided into the following 5 categories and associated with several risk factors (LOE 2, GOR B): (1) bladder storage problems, (2) NP, (3) global polyuria, (4) sleep disorders, and (5) mixed mechanisms. Research into pathophysiology remains a priority. Mechanisms underlying nocturia are poorly understood. Establishing why some patients manifest nocturia and not others with apparently similar predisposing factors, basic research into age-related circadian rhythms, effects on sleep quality, and the relationship between nocturia and restorative stages of sleep are a priority.4

ASSESSMENT Components of clinical assessment of nocturia are presented in Figure 1 and Table 2. UROLOGY


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Table 1. Representative studies demonstrating common risk factors for nocturia Risk Factor Medical conditions



Benign prostatic obstruction Depression



Asplund et al43



Yoshimura et al44


Neurologic disease

DasGupta and Fowler45 Tikkinen et al46


Torimoto et al47


Obesity and diabetes

Fitzgerald et al48


Overactive bladder and detrusor overactivity

Krystal et al49


Pelvic surgery

Thakar et al50


Half of the men with BPH reported nocturia of 2 voids/night Population-based study that demonstrated a significant association between major depression and nocturia HTN and CAD were both associated with nocturia, though, with a modest effect size Review of evidence linking multiple sclerosis to bladder dysfunction, including nocturia Parity, postpartum, and postmenopausal periods were associated with nocturia Demonstrated association between lower extremity edema and nocturnal urine volume, providing mechanistic basis for NP On multivariate regression, nocturia was associated with both type 2 diabetes and increased body mass index Nocturnal cystometrogram evidence of temporal relationship between nocturnal detrusor overactivity and night-time voiding Women reported fewer nightly voids after total or subtotal abdominal hysterectomy In a population-based study, history of hysterectomy was associated with nocturia Over 70% of men with PCa reported at least 2 voids/night, although it is unclear if such men are simply being screened more carefully, or if the 2 conditions are causally related No association between consumption of either substance and nocturia No association between smoking and nocturia Prospective study demonstrating a decrease in nocturnal voids after multicomponent lifestyle modification, including “moderate daily exercise” Higher odds of nocturia for black and Hispanic study participants vs whites

Menopause and hormonal therapy NP



Study Tikkinen et al


Alling et al51



Tikkinen et al42


Coffee and alcohol

Tikkinen et al42


Smoking Physical activity

Tikkinen et al42 Soda et al52

3727 56

Race/ethnicity and socioeconomic status

Fitzgerald et al48


BPH, benign prostatic hyperplasia; CAD, coronary artery disease; HTN, hypertension; NP, nocturnal polyuria; PCa, prostate cancer.

Conclusions and Recommendations The ICUD committee considered that validated symptom questionnaires are recommended as tools for initial and treatment response evaluation in the clinical setting (grade C). Questionnaires are unsuitable for the estimation of nocturnal voiding frequency (LOE 4, grade C). Nocturia-specific QoL questionnaires can be used to determine the impact of nocturia on QoL (LOE 4, grade C). Urinary diaries are essential in the analysis of nocturia (LOE 4, grade C). The International Consultation on Incontinence Questionnaire (ICIQ) bladder diary has been developed according to methodological requirements for assessment tools and has proceeded through contextual validations (LOE 2, grade B).9 Medication review is an important part of nocturia clinical assessment (grade A). Physical examination, flow rate testing, and urinalysis as relevant to assessment of LUTS help identify potential contributory mechanisms in some cases of nocturia (grade C). Postvoid residual measurement is directly relevant to nocturia (grade C). Routine use of invasive urodynamics, such as filling UROLOGY


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cystometry and pressure flow study, is not recommended (grade D). Blood chemistry examination is optional (grade CwD). Radiologic examinations or cystoscopy should only be used where indicated by the medical context, such as suspected malignant disease (grade D).4

TREATMENT Selected studies that were assigned LOEs by the ICUDSIU Consultation are briefly described. A particular issue in these studies is the extent to which any reduction in nocturia could be considered clinically beneficial. Small reductions in nocturia severity as compared against a control group could be statistically significant but may not be regarded as clinically significant. This is particularly the case if reduction compared with placebo is

Nocturia: Current Levels of Evidence and Recommendations From the International Consultation on Male Lower Urinary Tract Symptoms.

To evaluate published evidence on nocturia in men and derive expert recommendations...
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